1. Field of the Invention
The present invention relates to novel hydrochloride salts of a cross-linked glycopeptide-cephalosporin antibiotic compound and to pharmaceutical compositions containing such hydrochloride salts. This invention also relates to processes for preparing, and methods of using, such hydrochloride salts and compositions.
2. State of the Art
Cross-linked glycopeptide-cephalosporin antibiotics are known in the art. For example, such antibiotics are disclosed in U.S. Pat. Nos. 6,878,868 B2; 6,974,797 B2; 7,067,481 B2; 7,067,482 B2; 7,601,690 B2; and in Long et al., J. Antibiot. 61(10): 595-602 (2008); and Long et al., J. Antibiot. 61(10): 603-614 (2008). These antibiotics are reported to be useful for treating Gram-positive bacterial infections, including methicillin-resistant Staphylococci aureus (MRSA) infections. See, for example, Leuthner et al., Antimicrob. Agents Chemother. 2010, 54(9):3799; Hegde et al., Antimicrob. Agents Chemother. 2012, 56(3):1578; Blais et al., Antimicrob. Agents Chemother. 2012, 56(3):1584; and Tyrell et al., Antimicrob. Agents Chemother. 2012, 56(4):2194.
One such cross-linked glycopeptide-cephalosporin antibiotic is 26-[[[3-[[(Z)-[1-(2-amino-5-chloro-4-thiazolyl)-2-[[(6R,7R)-2-carboxy-8-oxo-3-(pyridiniomethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl]amino]-2-oxoethylidene]amino]oxy]propyl]amino]-carbonyl]-26-decarboxyvancomycin, which has the chemical structure:

This compound, also known as TD-1792, has been disclosed previously as either a tri(trifluoroacetic acid) salt or a trihydrochloride salt. See, for example, U.S. Pat. No. 6,974,797 B2 at column 34, line 60, to column 35, line 20. The disclosed salt forms, however, have several disadvantages.
First, perfluorocarboxylic acids, such as trifluoroacetic acid, have been reported to produce adverse hepatic effects when administered to rats. See, for example, Just et al., Hepatology, 9(4), 570-581 (1989). Therefore, a trifluoroacetic acid salt of this compound may not be pharmaceutically-acceptable for administration to patients.
Additionally, the trihydrochloride salt of this compound has been found to decompose significantly when stored at room temperature or even at refrigerated temperature (about 2 to about 8° C.). Therefore, the trihydrochloride salt may not be acceptable for use in a commercial formulation since pharmaceutical formulations are often stored for significant periods of time prior to use.
Accordingly, a need exists for new pharmaceutically-acceptable salt forms of this compound that have improved storage stability.
Also of interest are new pharmaceutical compositions containing such salts. Of particular interest are new pharmaceutical compositions that further improve the storage stability of the compound. The existing scientific literature, however, is often contradictory with regard to which excipients are useful for providing increased storage stability for pharmaceutical agents.
For example, EP 0 325 112 A1 teaches that cephalosporins are stabilized by dissolving the cephalosporin with lactose, glucose, sucrose or galactose (and optionally, glycine), and then drying the solution.
In contrast, U.S. Pat. No. 5,254,545 teaches that the pharmaceutical preparations of EP 0 325 112 A1 are not satisfactory to stabilize a particular cephalosporin compound and instead the cephalosporin is formulated with (i) lactose, (ii) citric acid or a sodium salt thereof and (iii) arginine or a hydrochloride thereof or sodium chloride to provide a stable preparation.
Moreover, with regard to the use of carbohydrates, Burgess et al., J. Chem. Soc. Perkin Trans. 2, 97 (1994) teaches that the decomposition of certain cephalosporins is catalyzed by glucose, galactose, maltose, sucrose, mannitol and α-methylglucoside in aqueous solutions at pH 9-11.
More recently, U.S. Patent Application Publication No. US 2010/010278 A1 discusses the advantages and disadvantages of various excipients used to prepare freeze-dried formulations of cephalosporins, such as polyols and amino acids (page 1, paragraphs 004 to 0019), and concludes that the scientific literature is contradictory and does not make it possible to predict which formulations will provide stability for the freeze-dried product (page 1, paragraph 0020). This document describes freeze-dried formulations for cephalosporin derivatives containing at least one stabilizer selected from carbohydrates, polyhydric alcohols and polyvinyl pyrrolidone.
With regard to pharmaceutical compositions for glycopeptides, EP 0 438 747 A1 discloses stabilized freeze-dried compositions of glycopeptides, such as orienticins A to D, chloroorienticins A to E, and vancomycin, comprising 0.05 parts by weight or more of one or more saccharides.
JP 414249 B2 discloses freeze-dried preparations of vancomycin comprising amino acids selected from arginine, alanine, aspartic acid, histidine and glycine.
Additionally, JP 2010105965 A discloses preparations of vancomycin containing water-soluble acid amides, such as nicotinamide.
Thus, a wide variety of excipients have been disclosed for use in formulating cephalosporins and glycopeptides. The scientific literature, however, is often contradictory as to which excipient to use with a particular pharmaceutical agent. As a result, identifying an excipient or combinations of excipients that improves the storage stability of a cross-linked cephalosporin-glycopeptide is particularly challenging since such compounds contain both cephalosporin and glycopeptide moieties in the same molecule.